| Project/Area Number |
13670543
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Nagoya City University |
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Principal Investigator |
JOH Takashi Nagoya city University, Graduate School of Medical Siences, associate professor, 大学院・医学研究科, 助教授 (30231369)
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| Co-Investigator(Kenkyū-buntansha) |
NAKANISHI Makoto Nagoya City University, Graduate School of Medical Sciences, Professor, 大学院・医学研究科, 教授 (40217774)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2002: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2001: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | p53 / Chk2 (hCds1) / cell cycle / a poptosis / DNA damage / Chk2(hCds1) / chk2 / 細胞周期 / NF-Y / 胃癌 |
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| Research Abstract |
The kinase Chk2 and tumor suppressor p53 participate in an in-defined regulatory interaction in mammalian cells. The abundance of Chk2 mRNA and protein has now been shown to be decreased by the induction of p53 in Saos2 cells. Ionizing radiation also triggered the phosphorylation and subsequent down-regulation of Chk2 in human fibroblasts ; irradiation of HeLa cells, which lack functional p53, induced Chk2 phosphorylation but not its down-regulation. Reporter gene assays in A172 cells revealed that wild-type p53 repressed, whereas a dominant negative p53 mutant increased, the activity of the human Chkk2 gene promoter. Mutational analysis showed that a CCAAT box located between nucleotides -152〜-138 of the promoter was responsible for its negative regulation by p53. Electrophoretic mobility-shift assays demonstrated that the transcription factor NF-Y binds to this CCAAT sequence. A dominant negative mutant of NF-Y abolished the effect of p53 on Chk2 promoter activity. Finally, expression of Chk2 under the control of a p53-insensitive promoter in A172 cells delayed reentry into the cell cycle after G2-M arrest induced by ionizing irradiation. These results suggest that p53 negatively regulates Chk2 gene transcription through modulation of NF-Y function, and that this regulation is important for reentry of cells into the cell cycle after DNA damage.
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